Sex Differences in Acute Pain and Analgesic Responses: Psychosocial and Genetic Influences ABSTRACT: Pain is one of the most costly and pervasive public health problems, with women and minorities facing increased risk for under-treated and mismanaged pain. Women, compared to men, report more frequent and intense pain and have increased prevalence of debilitating pain across a multitude of conditions. Women also represent the majority of the 40 million outpatient and ambulatory surgeries conducted each year. Acute post- operative pain and under-treatment of pain are well-documented and lead to prolonged recovery and potentially to development of chronic long-term pain conditions. Despite incongruent findings of sex differences in analgesic efficacy, consistent reports show that women experience between 30%-75% more adverse drug reactions (ADRs) compared to men. ADRs can lead to life-threatening complications, discontinuation of pain treatment, prolonged recovery and non-compliance. Recent pharmacogenomic studies have demonstrated that genotype may contribute to sex differences in pharmacokinetic (PK) and pharmacodynamic (PD) responses to certain drugs. Genetic and nongenetic contributions to sex differences in opioid analgesia, related side effects and treatment outcome have received limited attention in the field of pain research. This study will use a common acute clinical pain model to identify and characterize psychosocial, physiological and genetic factors that contribute to sex differences in pain perception, analgesia and side effects. Aim 1 will determine sex differences in perceptual and physiological responses to acute post-operative pain and will examine how those are related to genetic, pre-operative psychophysical and psychosocial factors. Aim 2 will determine sex differences in opioid analgesia and side effects and will examine genetic, PK, PD, and psychosocial factors that explain group differences in analgesic responses. 140 male and female patients (age range 16-45) who undergo third molar extraction will be included in this study. Preoperatively, we will assess experimental pain responses and psychosocial measures. We will monitor post-operative pain levels along with PK/PD responses to the opioid fentanyl. We will examine sex differences in post-operative pain, analgesic responses and side effects immediately and for several hours post-surgery and for 3 days post-procedure. The study is designed to build a foundation for a R01 grant proposal supporting an independent line of clinically-relevant experimental pain research. This project will enhance understanding of translational research in pain as well as biopsychosocial factors that contribute to health disparities in pain and its treatment, particularly for women. Additionally, this study will provide insight into the complex genetic, PK/PD processes involved in post- operative pain and analgesic responses and will elucidate biopsychosocial contributions to sex differences in pain and side effects. The ultimate goal is to develop translational research that will reduce the increased burden of clinical pain in women through the development of tailored interventions designed to enhance the quality of life for women, consistent with priorities of the NIH Office of Research on Women's Health. PUBLIC HEALTH RELEVANCE: Pain is one of the most costly and pervasive public health problems in the United States, and women are at increased risk for under-treatment of pain. This study will use a common acute clinical pain model to identify and characterize psychosocial, physiological and genetic factors that contribute to sex differences in pain perception, analgesia and side effects. The ultimate goal is to develop translational research that will reduce the increased burden of clinical pain in women through the development of tailored interventions designed to enhance the quality of life for women, consistent with priorities of the NIH Office of Research on Women's Health.